Metallic structures incorporating bioactive materials and methods for creating the same

ABSTRACT

One embodiment of the invention is directed to a method comprising providing an electrochemical solution comprising metal ions and a bioactive material such as bioactive molecules, and then contacting the electrochemical solution and a substrate. A bioactive composite structure is formed on the substrate using an electrochemical process, where the bioactive composite structure includes a metal matrix and the bioactive material within the metal matrix.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of the filing dates of the followingU.S. Provisional Patent Applications: 60/333,523, filed Nov. 28, 2001,and 60/364,083 filed Mar. 15, 2002. This application also claims thebenefit of the filing date of U.S. patent application Ser. No.10/196,296, filed on Jul. 15, 2002. All of these U.S. PatentApplications are herein incorporated by reference in their entirety forall purposes.

BACKGROUND OF THE INVENTION

Medical devices encompass a wide array of therapeutic, prophylactic, ordiagnostic tools, typically providing certain mechanical, electrical,electromechanical, or other structural properties designed to conductparticular medical procedures on or in a patient's body. Often, asimplants in particular (either temporary or permanent, though inparticular permanent), medical device designs are also intended toinclude characteristics that are sufficiently biocompatible to beacceptable by the host body, else the body may reject or otherwiserespond to the device with an undesired result. In particular, medicaldevices often are designed to have surface characteristics such that thedevice-tissue interactions at these surfaces are optimized. Accordingly,significant research and development into surface modifications andmaterials to provide optimal results. In particular, coatings have beenthe topic of significant interest for providing an external surfacelayer on medical devices in order to achieve the desired device-tissueinterface.

Many different medical devices, and related systems and methods, havealso been disclosed for locally delivering bioactive materials into oronto various regions of the body, such as lumens, cavities, tissues, orother spaces, structures, or regions. Such bioactive materials includefor example drugs (e.g. chemical or biological compounds, etc.) thatexhibit therapeutic effects relative to medical conditions, such asshort-term therapy drugs as well as long-term therapy, such as hormonaltreatment.

Various different types medical device systems and methods have beenpreviously disclosed for locally delivering bioactive materials intoremote regions of the body (e.g. lumen, cavity, tissue, or other bodyregion or space) in order to locally achieve the intended therapeutic,prophylactic, or diagnostic effect there.

One particular type of medical device that has become the topic of muchresearch and commercial development for delivering bioactive agents suchas drugs is stents. Of particular interest has been endolumenal stentsof the types that most typically form cylindrical or tubular walls thatare inserted into body lumens and engage their walls to prevent blockageor collapse, e.g. to maintain lumen patency. Such stents arepredominantly used in the vascular system, e.g., the coronary,peripheral and cerebrovascular systems. The most common stents in usetoday are produced from stainless steel or nickel-titanium alloy (e.g.Nitinol™), although different alloys have also been disclosed, such ascobalt-chromium alloys which have been given much attention in recentyears. Such endovascular stents are most typically used in percutaneoustranslumenal interventional procedures to treat diseases such ascoronary artery disease, peripheral vascular disease, andcerebrovascular disease.

Stents are used in other body lumens as well, including for example thehepatobiliary system. Indications for hepatobiliary stents includestrictures and malignancy. Such stents are often observed to havelimited effect as long-term solutions. Permanent metal stents in thehepatobiliary system are placed mostly for palliative treatment andusually in patients who have less than six months to live.

Notwithstanding the various benefits observed with the wide adoption ofconventional stenting, various shortcomings have been observed. In onesignificant regard, unfortunate and harmful medical conditions have beenobserved in relation to stent implants within lumens, in particular withrespect to intravascular stents. One such response is the formation ofthrombus on or around a stent, e.g. in the case of intravascularstenting, which may cause local occlusion or release of occlusivethromboembolism causing downstream ischemia. Another significant exampleis the tendency for a lumen to re-narrow or “restenose” despitestenting. Research into the pathophysiology of “restenosis” in bloodvessels has shown that there is smooth muscle cell proliferation and/orthrombosis shortly after a stent is placed within a vessel lumen. Atpresent, the rate of restenosis, or failure, is 20-50% at six months,necessitating re-stenting and/or surgical correction. Over one millionprocedures are performed per year to open the coronary arteries, evenafter stents are placed within them.

In recent years, much research and development in the field of stentshas been directed toward adapting them to release bioactive materials asanti-restenosis agents in order to prevent the various side effectsobserved with conventional un-coated stents, such as thrombosis and/orrestenosis. These stents are generally referred to as “drug elutingstents.” Several types of anti-restenosis agents have been investigatedfor use in drug eluting stents, including anti-coagulation agents,though most particularly the type which target smooth muscle cellmitosis, migration, and proliferation as the most significant observedprocess of restenosis. For example, some stents release drugs such asrapamycin or paclitaxel into surrounding lumenal wall tissues to combatrestenosis.

Many different modes have been previously disclosed for adapting stentsto release anti-restenosis drugs as drug eluting stents. Certainexamples include conventional or specially adapted stents in combinationwith an outer jacket or other composite of stent plus an additionalsleeve or member that holds and releases the drug, such as “coveredstents.” Many other recent advances have been directed toward coatingthe drug onto the outer surface of the stent itself, such as onto thetypical networked metal strut scaffolding of the conventional stentdesigns.

In one particular example, a hydrophobic drug paclitaxel is coateddirectly onto the outer surface of the stent struts. According todisclosures related to this example, the highly hydrophobic nature ofthe drug allows the drug to remain on the stent during delivery andimplantation at the lesion site without significant “wash-out” in theaqueous blood pool environment. The drug allegedly then passivelyreleases into the wall.

Of significant interest in various drug eluting stents being developedhas been coating the outer surface of the networked stent struts with acoating specifically adapted to hold and release anti-restenosis agentsof interest. Many such coatings are polymers that perform such function,including degradable polymers that release the drug via degradation ofthe polymer, or polymers that are adapted to provide diffusion of thedrug therefrom into the surrounding liquid environment (e.g. oftennon-degradable polymers). More specific examples of degradable andnon-degradable polymers that have been used in drug eluting stentsinclude without limitation polylactic acid, polyglycolic acid, andpolymethylmethacrylate.

Polymer coatings for drug eluting stents have certain limitations, andin some regards problems, associated with drug storage and releasemedium on stents and on medical devices in general. Various examples ofsuch limitations have been observed.

According to one example, polymeric coatings typically release bioactivematerials relatively quickly. While this may be advantageous and desiredin many circumstances, for certain intended drug delivery modalitieslonger time periods for drug elution may be desired than is achievablewith such polymer coatings. In another regard, the degradation kineticsof polymers is often unpredictable, in particular from patient topatient. Consequently, it is difficult to predict how quickly abioactive material in a polymeric medium will be released by such apolymeric medium. If a drug releases from the medium too quickly or tooslowly, the intended therapeutic effect may not be achieved.

In another example, many polymeric materials, including the typespreviously disclosed for stent coating, have been observed to produce aninflammatory response. For example, certain polymeric coatings on stentsin vessels have been observed to produce an inflammatory response on thevessel's walls, exacerbating restenosis.

According to another example, adherence of a polymeric material to asubstantially different substrate, such as a metallic substrate, e.g. astent, is difficult to achieve in manufacturing and to maintain in vivo.Mismatched properties such as different thermal and/or mechanicalproperties between the polymeric material and the underlying substrate(e.g. expansion characteristics of metallic stents) contribute to thisdifficulty. Inadequate bonding/adhesion between the stent body and anoverlying polymeric material may result in the separation of these twostent components over time, an undesirable property in an implantedmedical device. In consideration of this limitation, many polymericcoatings must be modified to maximize adherence to the stent, and suchmodifications often result in compromised ability to hold and releasedrug.

A further example of the foregoing relates to a two-part polymericcoating previously disclosed for use in drug eluting stents. One part isprimarily intended to provide structure to the coating and adherencearound stent struts during use; the other part is primarily intended tohold and release the drug. In order to achieve the requisite integrityof the coating on the stent, e.g. during expansion, the first part musthave a certain proportion to the second part in the two-part coating. Tothis end, the volume achievable with the second part of the coating islimited, and thus limiting the amount of drug that can be held andreleased.

A further limitation of polymer coatings for drug eluting stents is thedifficulty to achieve an even coating of a small metallic substrate witha polymeric material. As a small metallic object such as a stent is madesmaller (e.g., less than 3 mm in diameter), it becomes more difficult tocoat it evenly with a polymeric material. When the polymer is deposited,because it is viscous, it is difficult to evenly coat the object andfaithfully replicate its form. This is particularly challenging atvarious regions of a stent, such as at apices of bends in or bondsbetween stent struts where viscous materials may accumulate undersurface tension. Where unwanted polymer build-up results, folding andexpansion characteristics of the coated stent may be compromised. Inaddition, to the extent the polymer is holding and releasing drug,uneven coating corresponds to uneven and unpredictable drug deliveryalong and around the stent. To the extent dosing of drug is important topredict along the tissue engaged by the stent, increased or decreaseddose from the intended baseline may compromise the intended effects ofthe drug. Much research and development has been directed towardovercoming this limitation, and in many circumstances significantmodifications to or tightly held parameters of the polymeric coatingprocess, or addition of process steps, must be made to achieveacceptably even coatings.

Still a further exemplary limitation of polymeric drug coatings,polymeric storage and release media are typically large and bulkyrelative to their bioactive material storage capacity. In one regard,stents are designed with particular strut thicknesses and undulatingdesigns so as to maximize mechanical support properties at the vesselwall while minimizing size for profile considerations during delivery toand across a lesion and also to minimize turbulence along the luminalwall in a flowing blood field. Polymer coatings for drug eluting stentsare applied over these stent struts, and increase the size of theresulting coated strut. Such increase is directly proportional to theamount of coating necessary to hold the requisite volume of drug for theintended therapeutic or prophylactic effect. It would be desirable ifthe storage density of bioactive material storage medium could beincreased so that an intended volume of bioactive material could bereleased, often over a long period of time, while minimizing the bulk ofthe release media.

According to another significant limitation, polymeric coatings aretypically limited in their ability to be processed with, hold, orrelease bioactive agents of only particular types. Whereas bioactiveagents may be hydrophobic, hydrophilic, organic, inorganic, or otherwisedistinguishable in structure and activity, polymeric coatings often aresuitable for the desired interactions with only certain species of theseclasses. Therefore, certain drugs may not work with a particularcoating, and certain combinations or “cocktails” of multiple drugs cannot be coated onto the same substrate using the same coating. However,it would be desirable for a coating to work with a wide variety of typesof bioactive agents, in particular where a “cocktail” of multiple agentsis desired to be coated onto the same substrate such as a stent.

Still further limitations of polymeric coatings for medical devicesabound. For example, when delivering a bioactive material to a patientover a longer time period, particularly in an in vivo environment, thebioactive material needs to be stabilized. Some polymeric materials maynot provide for a stable storage environment for the bioactive material,in particular when liquid is able to seep into the polymeric material.In another example, polymers having relatively large pores can protectmicro-organisms in the interstices of the polymeric release medium, thusincreasing the risk of infection. In another example, certain polymericcoatings requiring processing parameters and/or materials (e.g.temperatures, solvents, or other aspects) which may be harmful to theintended drug to be held and released by the coating. Thus, multiplesteps must be included in the manufacturing process of the drug elutingstent or other medical device in order to get the polymer coated and thedrug into the polymer. According to yet another example, polymercoatings currently under development contribute bulk but do notcontribute to the major function of the stent, which is to provide astructural support to prop open the body lumen. It would further bedesirable if the storage medium for the bioactive material contributedto the mechanical strength of the object.

Furthermore, underlying substrates to be coated often require electricalsurface conductivity, such as in the case of electrodes - many polymersdo not provide for such conductivity, and such polymers may not besuitable to hold and release certain drugs. Alternatively, polymercoatings must be modified to provide for such conductivity, which mayimpact the other intended characteristics and complexity. Still further,coated devices may benefit from enhanced radiopacity wherever possible,such as for example nickel-titanium (e.g. NiTi stents). Most polymercoatings, in particular for drug eluting stents or otherwise coatingbioactive agents, do not provide this benefit or otherwise would requiresignificant modification to provide for radiopacity. It would bedesirable for a medical device coating, in particular that is adapted tohold and/or release bioactive agents, to provide further benefits suchas electrical surface conductivity or radiopacity.

Notwithstanding the significant prevalence of polymeric coatings in drugeluting stent research and development, other modalities have also beendisclosed for adapting stents and other medical devices to hold andrelease bioactive agents. In one regard, certain prior disclosuresattempt to deposit drugs into wells, grooves, or other cavities orreservoirs formed into the surface of the medical device itself forholding and releasing bioactive agents such as drugs. Other examples ofcoatings that have been disclosed for use in drug eluting stents inparticular include for example ceramics and hydrogels.

At least one additional disclosed example provides a sintered metallicstructure intended to provide a porous surface for delivering atherapeutic agent. Sintering generally involves fusing small particlesof metal using heat and/or pressure to weld them together. Poroussintered metallic structures typically have relatively large pores. Whena bioactive material is loaded into the pores of a sintered metallicstructure, the larger pore size can cause the biologically activematerial to be released very quickly. Also, because a relatively hightemperature is used to form a sintered structure, a bioactive materialincluding biologically active molecules generally must be loaded intothe sintered structure after the porous structure is formed, whereas“co-deposition” is often not possible as the bioactive agent woulddenature or otherwise be damaged from the heat. This method is generallytime consuming, and may in some circumstances be difficult to impregnatethe pre-formed pores of the sintered structure with certain biologicallyactive molecules. Consequently, it is difficult to fully load thesintered structure with them. When impregnating a sintered structure,the bioactive molecules may be in a carrier such as water or othersubstance. The surface tension of the carrier may preclude thebiologically active molecules from thoroughly impregnating the sinteredstructure. As a result, the sintered structure may not be fully loadedwith the biologically active molecules.

For further illustration, one previously disclosed example is intendedto load a therapeutic agent in a fluid form into a previously sinteredstent by immersing the sintered stent in a medicated solution. Thetherapeutic agent may be dissolved in a solvent or suspended in a liquidmixture. An average pore size that is more than ten times the particlesize of a suspended therapeutic agent is an intended result of sinteringaccording to this disclosure. Moreover, use of pressure is furtherdisclosed to aid the passage of medicated fluid into the porous cavitiesof the stent.

As noted above, it would be desirable to have ability to increase thebioactive material storage capacity in a bioactive composite material sothat, for example, the bioactive material can be released to a patientover a long period of time. In another regard, because a liquid (blood,water, etc.) can enter into the pores of the material, the stability ofthe bioactive materials is limited. Such high temperatures also renderthis process incompatible with certain underlying substrates that may bestructurally or functionally degraded by the heat exposure, such as forexample certain polymeric and other material substrates, and inparticular nickel-titanium substrates (e.g. NiTi stents), which havetrained material properties such as superelasticity or shape memory thatmight be diminished under the heat exposure.

Still further previously disclosed coating examples use electroplatingmethods for coating metals onto surfaces, such as onto substrates toform or coat medical devices. Electroplating generally involves exposinga surface to an environment that includes metal particles. An electricalcharge or current is applied and results in deposition of the metal ontothe surface. While electroplating metals to form structures associatedwith medical devices may provide benefits in certain situations, incertain circumstances it would be beneficial if such metal depositioncould be achieved without requiring the formation of an electricalcircuit and/or application of electrical current.

Further examples of coatings intended for use for drug eluting stentsrequire formation of multiple coating materials, such as in multiplelayers on a substrate. In one such example, one layer may be used foradhesion to a substrate, the other for holding and releasing drug. Inanother example, one coating may hold one type of bioactive material,the other holds another type. In another example, one coating layerholds drug onto a stent, an additional top layer envelops the firstlayer and provides for delayed release of the drug not otherwiseachievable via the first layer. Another example provides what isintended to be a biomimetic coating with multiple layers intended to bemimic cell wall structures intended to enhance biocompatibility of thecoated surface.

These other examples of previously disclosed modes for coating oradapting medical devices for release of bioactive agents suffer fromrespective various limitations similar to one or more of those providedabove with respect to polymeric coatings, including without limitation:processing limitations in relation to underlying substrate or bioactiveagent to be coated; even distribution of coating or drug; adhesion;biocompatibility (e.g. toxicity, or other adverse biological response);complexity of processing; size; density and thus volume of drug that canbe held and released; timing of drug release; high electrical impedance;low radiopacity; or impact of the coating on the underlying substrate'sintended function (e.g. mechanical properties, expansioncharacteristics, electrical surface conduction, radiopacity, etc.).

Further more detailed examples of medical devices or other structures ormethods providing general background with respect to this descriptionare variously disclosed in the following issued U.S. Patents: U.S. Pat.No. 4,358,922 to Feldstein; U.S. Pat. No. 4,374,669 to Mac Gregor; U.S.Pat. No. 4,397,812 to Mallory, Jr.; U.S. Pat. No. 4,547,407 to Spencer,Jr.; U.S. Pat. No. 4,729,871 to Morimoto; U.S. Pat. No. 4,917,895 to Leeet al.; U.S. Pat. No. 5,145,517 to Feldstein et al.; U.S. Pat. No.5,338,433 to Maybee et al.; U.S. Pat. No. 5,464,524 to Ogiwara et al.;U.S. Pat. No. 5,616,608 to Kinsella et al.; U.S. Pat. No. 5,624,411 toTuch; U.S. Pat. No. 5,700,286 to Tartaglia et al.; U.S. Pat. No.5,725,572 to Lam et al.; U.S. Pat. No. 5,772,864 to Moller et al.; U.S.Pat. No. 5,843,172 to Yan et al.; U.S. Pat. No. 5,873,904 to Ragheb etal.; U.S. Pat. No. 5,958,430 to Campbell et al.; U.S. Pat. No. 5,972,027to Johnson; U.S. Pat. No. 5,976,169 to Imran; U.S. Pat. No. 6,019,784 toHines; U.S. Pat. No. 6,042,875 to Ding et al.; U.S. Pat. No. 6,123,861to Santini, Jr. et al; 6,143,037 to Goldstein et al.; U.S. Pat. No.6,174,329 to Callol et al.; U.S. Pat. No. 6,180,162 to Shigeru et al.;U.S. Pat. No. 6,231,600 to Zhong; U.S. Pat. No. 6,240,616 to Yan; U.S.Pat. No. 6,253,443 to Johnson; U.S. Pat. No. 6,258,121 to Yang et al.;U.S. Pat. No. 6,273,913 to Wright et al.; U.S. Pat. No. 6,280,411 toLennox; U.S. Pat. No. 6,287,249 to Tam et al.; U.S. Pat. No. 6,287,285to Michal et al.; U.S. Pat. No. 6,306,166 to Barry et al.; U.S. Pat. No.6,309,380 to Larson et al.; U.S. Pat. No. 6,315,794 to Richter; U.S.Pat. No. 6,322,847 to Zhong et al.; and U.S. Pat. No. 6,447,664 toTaskovics et al. The disclosures of these references are hereinincorporated in their entirety by reference thereto.

Additional examples are also variously disclosed in the following U.S.Patent Application Publications: U.S. 2001/0032014 to Yang et al.; andU.S. 2002/0098278 to Bates et al. The disclosures of these referencesare herein incorporated in their entirety by reference thereto.

Still further examples are variously disclosed in Published PCT PatentApplications having the following International Publication Numbers: WO89/03232 to Bar-Shalom et al.; WO 91/12779 to Wolff et al.; WO 91/17286to Tarasevich et al.; WO 93/19803 to Heath et al.; WO 98/36784 to Raghebet al.; WO 99/08729 to Barry et al.; WO 99/25272 to Richter et al.; WO00/10622 to Ragheb et al.; WO 00/21584 to Barry et al.; WO 00/27445 toBoock et al; WO 00/29501 to Hampikian et al.; WO 00/32238 to Palasis etal.; WO 00/32255 to Kamath et al.; WO 01/01890 to Yang et al.; WO01/14617 to Leclerc et al.; WO 01/15751 to Ahola et al.; WO 01/70294 toEidenschink et al.; WO 01/87372 to Kopia et al.; and WO 02/058775 toSegal et al. The disclosures of these references are herein incorporatedin their entirety by reference thereto.

Still further examples are disclosed in the following Published EuropeanPatent Applications: 0 568 310 to Mitchell et al.; EP 0 734 721 to Euryet al.; EP 0 747 069 to Fearnot et al.; EP 0 950 386 to Wright et al.The disclosures of these references are herein incorporated in theirentirety by reference thereto.

Notwithstanding certain benefits that may be provided by the foregoingexamples for forming or coating structures for use in medical devices,it would be beneficial if a coating process and matrix could be providedthat overcomes one or more of the limitations of these prior attempts,such as for example (but without limitation) being able to providesmaller and/or more densely packed surface pores in certaincircumstances, to deposit a bioactive material in the coating during thecoating process, to process at reduced temperatures, to providepredictable and even coating coverage on substrates, to provide improvedadhesion on difficult substrates (e.g. nickel titanium), etc.

The present invention addresses the various limitations and needs thatstill exist in view of the previous attempts noted above and otherwise,individually and collectively.

SUMMARY OF THE INVENTION

Certain aspects of the invention are directed to structures, methods,and devices that include a metallic matrix including a bioactivematerial (e.g., a drug). In some modes according to these aspects, thebioactive material is contained within a metallic matrix. In someembodiments, the matrix can be crystalline and can have grainboundaries. Diffusion of the bioactive material according to theseembodiments can occur for example along the grain boundaries andcrystallites of the metal. The bioactive material can be within, forexample, nanometer and sub-nanometer sized regions within the metallicmatrix, such as in void regions. In certain embodiments, the bioactivematerial can be stored in a metallic matrix and can then be releasedfrom the metallic matrix. The bioactive material may diffuse through themetallic matrix or the metallic matrix could erode (actively and/orpassively) to release the bioactive material over time. This can be donewithout using a polymeric storage and release medium for the bioactivematerial.

One embodiment according to these aspects is directed to a methodcomprising: (a) providing an electrochemical solution comprising metalions and bioactive materials; (b) contacting the electrochemicalsolution and a substrate; and (c) forming a bioactive compositestructure on the substrate using an electrochemical process, wherein thebioactive composite structure includes a metal matrix and the bioactivemolecules within the metal matrix.

Another embodiment according to these aspects is directed to a bioactivecomposite structure comprising: (a) a metal matrix, wherein the metalmatrix is formed using an electrochemical process; and (b) bioactivemolecules within the metal matrix.

Another embodiment according to these aspects is directed to a medicaldevice comprising: a bioactive composite structure comprising a firstmaterial, a second material derived from a reducing agent relative tothe first material, and a bioactive material. The second material, maybe, for example, phosphorous that is derived from a reducing agent suchas sodium hypophosphite. In some embodiments, the first material is ametallic material (e.g., nickel, cobalt, etc.) and the first metallicmaterial and second material may form a metallic matrix whichincorporates the bioactive material.

Other aspects of the invention are directed to various medical devicesthat incorporate the bioactive composite structure or are whollycomprised of the bioactive composite structure.

Other aspects of the invention are directed to methods of using thebioactive composite structure.

Another aspect of the invention provides a medical device having asubstrate and a coating on the substrate that comprises nickel.According to one mode of this aspect, the substrate also comprisesnickel. According to one highly beneficial embodiment of this mode, thesubstrate comprises a nickel-titanium alloy. According to anotherembodiment, the coated substrate is characterized as releasingsubstantially less nickel in an aqueous environment than is released bythe nickel-containing substrate alone without the nickel-containingcoating. According to one highly beneficial variation of thisembodiment, the coated substrate is characterized as releasing at leasttwenty-five percent less nickel than the uncoated substrate. In anothervariation, the coated substrate is characterized as releasing at leastfifty percent less nickel than the uncoated substrate. According toanother mode of this aspect, the substrate comprises a stent. Accordingto one embodiment of this mode, the stent comprises a network ofinterconnected nickel-titanium struts. According to another embodimentof this mode, the stent comprises a network of interconnected strutsconstructed from a nickel-titanium alloy

Another aspect of the invention provides an endolumenal stent having astent wall with an outer surface and a coating on the stent wall thatcomprises a metal, a reducing agent of the metal, and a bioactive agent.According to one mode of this aspect, the metal comprises a bi-valentmetal ion in aqueous solution. According to another mode, the metalcomprises a tri-valent metal ion in aqueous solution.

Another aspect of the invention is a medical device having a substratewith an outer coating that comprises a first material, a secondmaterial, and a bioactive agent, wherein the first and second materialsare characterized as forming cations and anions sufficient to form anelectrochemical deposition process when in an aqueous solution.

Another aspect of the invention is a method for coating a medical devicecomprising: providing a substrate with an outer surface; and forming acoating layer onto the outer surface of the substrate with a coatingmaterial while depositing a bioactive agent within the coating layer.One mode of this aspect further includes: releasing the bioactive agentfrom the coating layer. One embodiment of this mode further includes:while releasing the bioactive agent from the coating layer,substantially maintaining the coating material in the coating layer.Another mode of this aspect includes forming the coating layer withoutsubstantially heating the outer surface which in one embodiment includesnot heating the outer surface above 120 degrees Fahrenheit. Another modeof this aspect includes forming the coating layer without using apolymeric material. Another mode of this aspect includes: forming thecoating material with a first material and a second material that is areducing agent of the first material (i.e. transfers electrons to thefirst material). One embodiment of this mode includes providing a metalion as the first material, and providing a negative ion as the secondmaterial which can transfer negative charge to the first material inorder to reduce it to the non-charged state.

Another mode of this aspect includes forming a solution of a firstcoating material, a second coating material, and the bioactive material,wherein the first and second coating materials together form the coatingmaterial in the coating layer. One embodiment of this mode furtherincludes contacting the solution with the substrate. One variation ofthis embodiment includes submerging the substrate within a bath of thesolution. Another further highly beneficial variation of this embodimentincludes passively forming the coating layer with the solutioncontacting the substrate.

Another aspect includes a solution that is useful in coating a substratesuch as a medical device, comprising: a solution of at least one coatingmaterial and at least one bioactive material. According to one mode ofthis aspect, the at least one coating material comprises a metal ion.According to another mode of this aspect, the bioactive materialcomprises an anti-restenosis agent. According to one beneficialembodiment of this mode, the anti-restenosis agent comprises at leastone of: anti-proliferative agent, anti-mitotic agent, anti-migrationagent, anti-inflammatory agent, adhesion inhibitor, platelet aggregationinhibitor, or anticoagulant agent. According to another mode, thesolution comprises an aqueous liquid, and the at least one coatingmaterial comprises a first material that is an anion and a secondmaterial that is a cation in the aqueous liquid. According to onefurther embodiment of this mode, the first and second materials areadapted to form an electrochemically deposited film on the substrate. Inone highly beneficial variation of this embodiment, the first and secondmaterials are adapted to form an electrolessly, electrochemicallydeposited film on the substrate.

Another aspect of the invention includes a medical device with asubstrate and a coating layer on the substrate that increases theradiopacity of the medical device. In one mode, the coating layerincludes a metal that increases the radiopacity of the medical device.In another mode, the substrate is a metal substrate. In another mode,the substrate is a stent. In another mode, the coating layer includes afirst coating material and a second coating material, wherein at leastone of the first and second coating materials increases the radiopacityof the substrate. In another mode, the coating layer includes abioactive material. In one embodiment of this mode, the coating layerfurther includes first and second coating materials in combination withthe bioactive material. In one highly beneficial further variation ofthis embodiment, the coating layer is a composite matrix with the firstand second coating materials and the bioactive material. In still afurther feature of this embodiment, at least one of the first and secondcoating materials may be a metal. In a further feature that may bebeneficially included for this composite matrix variation, the substrateis a stent and the bioactive material is an anti-restenosis material.

Another aspect of the invention is a medical device with an outersurface that includes a non-sintered composite metallic matrix thatincludes at least one metal and a bioactive material. The medical devicematrix is adapted to release the bioactive material within the body.

Another aspect of the invention is a medical device with an outersurface that includes a metal matrix and pores containing bioactivematerial that are less than about 1 micron in diameter. In one mode, thebioactive material is an anti-restenosis material. In another mode, themedical device comprises a stent and the outer surface is located on thestent struts. In another mode, the pores are less than about 100angstroms in diameter.

Another aspect of the invention is a medical device with a substratethat includes a metal and a coating on the substrate that includes thesame metal. In one mode of this aspect, the metal is nickel. In oneembodiment of this mode, the substrate is a nickel-titanium alloy. Inone further variation of this embodiment, the coating does not containtitanium. In another mode, the metal is cobalt. In one embodiment ofthis mode, the substrate contains cobalt and chromium. In one variationthat may be beneficially applied to this embodiment, the coatingcontains both cobalt and chromium. In another mode, the substrateincludes an alloy of the metal and a second metal, and the coating doesnot include the second metal. In another mode, the coating includes abioactive agent. In one highly beneficial embodiment of this mode, thebioactive agent is an anti-restenosis agent. In another highlybeneficial mode, the substrate is a stent.

Another aspect of the invention is a medical device with a substrate anda coating on the substrate that is adapted to contain a variety of typesof bioactive materials. In one mode, the coating is adapted to containeither or both of water soluble or water insoluble bioactive materials.In another mode, the coating is adapted to contain either or both oforganic or inorganic materials. In another mode, the substrate is astent. In another mode, at least one type of the variety of bioactivematerials is contained within the coating.

Another aspect of the invention is a medical device with a substrate anda coating on the substrate that includes a metal matrix. The metalmatrix includes a metal and also is also characterized according to atleast one of the following characteristics: a bioactive material is inthe metal matrix; or (ii) a relatively radiopaque material relative tothe substrate is in the metal matrix; or (iii) the metal matrix is anon-sintered, non-electroplated, non-radioactive metal matrix; or (iv)the metal matrix is an electroless electrochemically deposited metalmatrix; or (v) a material derived from a reducing agent of a metal ionformed by the metal in an aqueous fluid is in the metal matrix.

Such a medical device according to this aspect that has a coatedsubstrate exhibiting any one of these characteristics is considered ahighly beneficial independent aspect of the invention, whereascombinations incorporating all or any two or more of thesecharacteristics are further considered independently beneficial aspects.Accordingly, one beneficial aspect of the invention is a medical devicewith a substrate that is coated by a metal matrix having a bioactivematerial is in the metal matrix. Another beneficial aspect is a medicaldevice with a substrate that is coated by a metal matrix having arelatively radiopaque material relative to the substrate is in the metalmatrix. Another beneficial aspect is a medical device with a substratethat is coated by a metal matrix that is non-sintered,non-electroplated, non-radioactive. Another beneficial aspect has ametal matrix coating that is electroless electrochemically deposited,and another aspect is a metal matrix coating that includes a first metalmaterial and a second material that is derived from a reducing agent ofa metal ion formed by the metal in an aqueous fluid solution.

Another aspect of the invention is a medical device with a substrateformed from at least two metals and a coating on the substrate. Thecoating is further characterized as having at least one of the followingcharacteristics: (i) the coating includes a first one of the two metalsin the substrate, and exhibits a substantially reduced rate of releaseof this first metal than would be released from the substrate alone in ablood environment; or (ii) the coating includes a first one of the twometals found in substrate, but does not include the second one of thetwo metals.

Such a medical device according to this aspect that has a coatedsubstrate exhibiting any one of these characteristics is considered ahighly beneficial independent aspect of the invention, whereascombinations incorporating all or any two or more of thesecharacteristics are further considered independently beneficial aspectsof the invention. Therefore, a beneficial aspect of the invention is amedical device with a substrate and a coating on the substrate thatincludes a first one of two metals in the substrate, and exhibits asubstantially reduced rate of release of this first metal than would bereleased from the substrate alone in a blood environment. Anotherbeneficial aspect is a medical device with a substrate that is coated bya coating that has a first one of two metals found in substrate, butwhich coating does not include the second one of the two metals

In one mode according to this aspect, the two metals in the substratecomprise the two most prevalent materials in the substrate. In anothermode, the two metals comprise two principal metals in a metal alloy thatmakes up the substrate. In further modes, other metals may be furtherprovided in the substrate or coating.

Another aspect of the invention is a medical device that includes asubstrate and a bioactive material. The substrate has an outer surfacethat is at least in part metal, and also has a plurality of regions thatare adapted to contain the bioactive material and to release thebioactive material from the substrate in the body of a patient. Thebioactive material is contained within the regions. The medical deviceaccording to this aspect is further characterized according to at leastone of the following characteristics of the regions in the outersurface: (i) they are sufficiently small to substantially prevent waterpenetration into the bioactive material contained therein when the outersurface is exposed to a blood environment in a patient; or (ii) theyhave a diameter of less than about 1 micron in diameter; or (iii) theyhave a diameter that is less than about ten times the size of thebioactive material. Such a medical device that has a coated substrateexhibiting any one of these characteristics is considered a highlybeneficial independent aspect of the invention, whereas combinationsincorporating all or any two or more of these characteristics arefurther considered independently beneficial aspects.

Another aspect of the invention is a medical device that includes abioactive composite structure with a metal matrix and a bioactivematerial in the metal matrix. The bioactive composite structure forms atleast a portion of a stent.

Another aspect of the invention is a medical device that includes asubstrate and a coating on the outer surface of the substrate. Thecoating according to this aspect is characterized as having one or moreof the following characteristics: (i) the coating has a thickness overthe outer surface of the substrate that is less than about 5 microns anda therapeutic level of bioactive material in the coating; or (ii) thecoating includes a metal matrix and a bioactive material in the metalmatrix; or (iii) the coating includes a non-electroplated metal matrix.The coated substrate according to this aspect is further characterizedas forming at least a portion of a stent.

Such a medical device according to this aspect that has a coatedsubstrate exhibiting any one of the characteristics just described isconsidered a highly beneficial independent aspect of the invention,whereas combinations incorporating all or any two or more of thesecharacteristics are further considered independently beneficial aspects.

Another aspect of the invention is a method for forming a medical deviceat least in part by forming a metal matrix according to a process thatincludes one or more of the following: (i) electroless electrochemicaldeposition of a metal and a second material derived from a reducingagent with respect to metal ions formed by the metal when in an aqueoussolution; or (ii) forming the metal matrix while depositing a bioactiveagent in the metal matrix; or (iii) forming the metal matrix as acoating on a substrate without using an applied electrical current andwithout sintering, or (iv) forming the metal matrix as a coating on asubstrate without using an applied electrical current and at atemperature that is less than about 120 degrees Fahrenheit. The methodaccording to this aspect further includes forming the metal matrix as atleast a portion of the medical device.

Such a method according to this aspect that includes a process forforming a metal matrix that exhibits any one of the characteristics justdescribed is considered a highly beneficial independent aspect of theinvention, whereas combinations incorporating all or any two or more ofthese characteristics are further considered independently beneficialaspects.

Another aspect of the invention is a method for manufacturing a medicalstent at least in part by forming a metal matrix with a process thatincludes one or more of the following: (i) forming the metal matrix as acoating on a substrate without using an applied electrical current, or(ii) depositing a bioactive material in the metal matrix. The methodaccording to this aspect further includes forming the metal matrix as atleast a portion of the stent. Further modes of this method includeperforming the process without sintering, or in a temperatureenvironment that is less than about 120 degrees Fahrenheit.

Another aspect of the invention is a solution for use in forming atleast a portion of a medical device. The solution according to thisaspect includes a bioactive material in combination with anothermaterial within a fluid that is adapted to form an electrochemicaldeposition of the bioactive material and the other material onto asubstrate contacted by the solution.

Various further modes of the invention that are beneficial furtheralternative embodiments of the aspects provided above include in onebeneficial example forming metal matrix structures in medical devicesthat include at least one of nickel, cobalt, or chromium in combinationwith at least one of phosphorous or boron. In more particular beneficialembodiments, nickel is provided in combination with phosphorous in ametal matrix (e.g. as an outer surface of a medical device such as astent), or cobalt and chromium may be provided in a metal matrix withphosphorous or boron.

Other various modes that may be also incorporated with the aspects aboveas further embodiments include combination of electrolesselectrochemical deposition with other deposition methods and/orresulting structures, such as for example sintering and/orelectroplating metals in combination with electroless electrochemicaldeposition of metal matrices. For example, multiple layers of metalmatrices may be formed by these various processes with a resultproviding beneficial composite structures. In still further examples,polymers, ceramics, hydrogels, or other coating materials and relatedprocesses may be combined with the various aspects above as furtherembodiments and variations that provide further independent benefitaccording to the invention.

Highly beneficial further modes applicable to the various aspects aboveprovide a medical device in the form of an implantable stent. Inexemplary embodiments, the stent includes the substrate in the form ofstruts that are interconnected in a network that forms an expandabletubular body adapted to hold a lumen open in the expanded condition.Various of the coatings, metal matrices, and substrates embodied by thevarious independent aspects have particularly beneficial applicationaccording to such stent modes.

Although medical devices such as stents are discussed in detail, it isunderstood that embodiments of the invention are not limited to stentsor for that matter, to macroscopic devices. For example, embodiments ofthe invention could be used in any device or material, regardless ofsize and includes artificial hearts, plates, screws, “MEMS”(microelectromechanical systems), and nanoparticle based materials andsystems, etc. Other examples of medical devices and materials accordingto embodiments of the invention are described below.

These and other aspects, modes, embodiments, variations, and features ofthe invention are described in further detail with reference to theFigures and the Detailed Description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic illustration of a substrate and a bioactivecomposite structure on the substrate.

FIG. 2 shows a schematic illustration of a portion of a bioactivecomposite structure containing a bioactive material.

FIG. 3 shows a device including a bioactive composite structure inbetween a substrate and a topcoat.

FIGS. 4(a)-4(c) show a stent being placed into a coronary artery.

FIG. 5 shows a flowchart illustrating an exemplary method according toan embodiment of the invention.

FIG. 6 shows a graph showing drug elution profiles associated withJohnson and Johnson Bx velocity stents (stainless steel) with bioactivecomposite structures according to embodiments of the invention.

FIG. 7 shows a graph showing drug elution profiles associated withstents made with nickel-titanium alloy and bioactive compositestructures according to embodiments of the invention.

DETAILED DESCRIPTION I. Definitions

Some terms that are used herein are described as follows.

The terms “anti-restenosis” as herein used in relation to compounds,agents, or other materials generally refer to those “bioactivematerials” (as defined immediately below) that at least in partcontribute to prevention or inhibition of a restenosis response tovascular injury related to an endolumenal intervention, such asangioplasty, atherectomy, stenting or other recanalization orendolumenal implant procedure. Examples of anti-restenosis agentsinclude anti-mitotic agents, anti-proliferative agents, anti-migratoryagents, anti-inflammatory agents, anti-thrombin agents (e.g. thrombininhibitors), anti-platelet aggregation agents (e.g. plateletadhesion/aggregation inhibitors), healing agents such asendothelialization promoters, or other agents mitigating, preventing, orotherwise intervening in the biological restenosis process.

The terms “bioactive material(s)” refer to a compound, agent, or anyother material that exhibits biologically relevant activity on or withina biological organism, including in particular activity that providestreatment, prophylaxis, or diagnosis of a medical condition related to abody of a patient, such as dysfunctional or abnormal conditionsassociated with the body's structures or functions, or conditionsresulting from or otherwise related to a medical procedure, e.g. amedical intervention.

Examples of bioactive materials include drugs for contraception andhormone replacement therapy, and for the treatment of diseases such asosteoporosis, cancer, epilepsy, Parkinson's disease and pain. Furtherexamples of bioactive materials include, without limitation:anti-inflammatory agents, anti-infective agents (e.g., antibiotics andantiviral agents), analgesics and analgesic combinations, antiasthmaticagents, anticonvulsants, antidepressants, antidiabetic agents,antineoplastics, anticancer agents, antipsychotics, and agents used forcardiovascular diseases, such as anti-restenosis compounds andanticoagulant compounds. Further examples of molecules useful asbioactive materials include: hormones, growth factors, growth factorproducing virus, growth factor inhibitors, growth factor receptors,antimetabolites, integrin blockers, or complete or partial functionalin-sense or anti-sense genes.

The following are further examples of different types of compounds thatmay be bioactive materials: inorganic, organic, or organometallic;hydrophilic or lipophilic; hydrophobic or lipophobic; water soluble orwater insoluble; peptides or proteins; polypeptides; polysaccharides(e.g. heparin); oligosaccharides; mono- or disaccharides; whereas any ofthe foregoing labels apply with respect to molecules, compounds, orother preparations or materials. Other examples include: livingmaterial, such as living or scenescant cells, bacterium, virus,plasmids, genes, other genetic material, or other components or partsthereof; and man-made particles or other materials, for example carryinga biologically relevant or active material.

Bioactive materials may also include precursor materials that exhibitthe relevant biological activity after being metabolized, broken-down(e.g. cleaving molecular components), or otherwise processed andmodified within the body. These may include such precursor materialsthat might otherwise be considered relatively biologically inert orotherwise not effective for a particular result related to the medicalcondition to be treated prior to such modification.

Combinations, blends, or other preparations of any of the foregoingexamples may be made and still be considered bioactive materials withinthe intended meaning. Aspects of the present invention directed towardbioactive materials may include any or all of the foregoing examples.

The term “electrochemical deposition” refers to both electrodeposition(electroplating) and electroless deposition (see method descriptionsbelow).

The term “medical device” refers to a device or structure that isforeign to a body of a living being, such as in particular a human body,but which is adapted for use in performing a therapeutic, prophylactic,or diagnostic function inside, on, or otherwise in relation to the bodyof a living being, such as in particular human beings. Medical devicesinclude for example many different types of permanent or temporaryimplants. Further illustrative examples of medical devices include butare not limited to: catheters; guidewires; coils; expandable memberdevices (e.g. balloons or cages); drug delivery apparatuses, includingfor example patches; vascular conduits, e.g. grafts, stent-grafts,fistulas; stents; grafts; plates; screws; spinal cages; dental implants;dental fillings; braces; artificial joints; embolic devices; ventricularassist devices; artificial hearts; heart valves; embolic filters (e.g.venous); staples; clips; sutures; prosthetic meshes; mapping; ablationor stimulating electrode devices; pacemakers; pacemaker leads;defibrillators; neurostimulators; neurostimulator leads; intrauterinedevices (“IUD's”); syringes; shunts; cannulas; and implantable orexternal sensors. Medical devices are not limited by size and includemicromechanical systems, and nanomechanical systems which perform afunction in or on the surface of the human body. Embodiments of theinvention include such medical devices.

The term “implants” refers to a category of medical devices, which areimplanted in a patient for some period of time. They can be diagnosticor therapeutic in nature, and long or short term, permanent ortemporary.

The term “self-assembly” refers to a nanofabrication process to form amaterial or coating, which proceeds spontaneously from a set ofingredients. A common self-assembly process includes the self-assemblyof an organic monolayer on a substrate. One example of this process isthe binding of linear organic molecules to a substrate. Each moleculecontains a thiol group (S-H moiety). The thiol group of each moleculecouples to the gold surface while the other end of the molecule extendsaway from the gold surface. The process of electroless deposition, whichcontinues spontaneously and auto-catalytically from a set ofingredients, may also be considered a self-assembly process.

The term “stents” refers to medical devices that are adapted to engagethe wall of a body lumen or interstitial tract in order to affect thepatency thereof, and may be either permanent or temporary implants.Stents are generally adjustable between a radially collapsed condition(e.g. for endolumenal delivery through a delivery catheter lumen) and aradially expanded condition (e.g. to radially engage the lumenal wall).Various types of expandable stents include a tubular or partiallytubular wall structure having a network of interconnected strutsseparated by voids, which structure may be cut from a tube, such as bylaser cutting or photoetching, or may be formed by securing adjacentshaped rings. Most common expandable stents are metallic (e.g. thestruts). Examples of different types of such expandable stents include:balloon expandable (e.g., stainless steel, or cobalt-chrome); and thosewhich are self expanding (e.g., nickel-titanium alloy such as Nitinol™).Stents may also be non-metallic, such as polymeric. Stents may also beconstructed as a helical or otherwise folded ribbon structuresreconfigurable between collapsed and expanded conditions for deliveryand implantation, and may be formed in a composite structure with othermaterials such as grafts to form stent-grafts (e.g. for treatingabdominal aortic aneurysms).

Stents may be used to maintain lumenal patency, such as for examplethose currently used in peripheral, coronary, and cerebrovascularvessels, the alimentary, hepatobiliary, and urologic systems, the liverparenchyma (e.g. porto-systemic shunts), and the spine (e.g., fusioncages). Conventional stents are typically greater than about 2 to 3millimeters, though smaller stents are contemplated, such as inparticular for certain particular indications. For example, stents maybe used in the interstitium to create conduits between the ventricles ofthe heart and coronary arteries, or between coronary arteries andcoronary veins. In the eye, stents may be used for the Canal of Schlemto treat glaucoma. Stents also may be used in order to occlude a lumen,such as for example to occlude fallopian tubes for fallopian tuballigation, feeder vessels to tumors, or aneurysms; such occlusive stentstypically include the addition of bioactive material such as fibrin tocause an occlusive thrombosis. Occlusive stents may be expanded withinthe lumen to be occluded, or may be contracted around the lumen fromoutside the vessel wall.

The term “electroforming” refers to a process in which electrochemicaldeposition processes are performed on a sacrificial substrate. After thedeposition process, the substrate is etched away, leaving a freestandingstructure.

II. Methods of Manufacture

Embodiments of the invention include methods of manufacturing bioactivecomposite materials. In one embodiment, the method includes providing anelectrochemical solution comprising metal ions and a bioactive material.The electrochemical solution may be an electroless deposition bath thatis formed using metal salts, a solvent, and a reducing agent, or aelectrodeposition bath which is formed with a cathode (the substrate fordeposition), an anode, and an electrolyte solution containing themetallic ions to be reduced. Complexing agents, stabilizers, and buffersmay also be present in the bath. After the electrochemical solution isformed, a substrate contacts the electrochemical solution. For example,the substrate may be immersed in a bath comprising the electrochemicalsolution.

Prior to contacting the electrochemical solution, the substrate can beprepared for the electrochemical process. In one preparation step, ananodic process is performed. In this process, the substrate is submergedin a hydrochloric acid bath. Current is passed through the solution,creating small pits in the substrate. Such pits promote adhesion. Also,a sensitizing agent and/or catalyst can be deposited on the substrate toassist in the creation of nucleation centers leading to the formation ofthe bioactive composite structure. Loosely adhered nucleation centerscan also be removed from the surface of the substrate using, forexample, a rinsing process.

After contacting the electrochemical solution, a bioactive compositestructure is formed on the substrate using an electrochemical process.The electrochemical process may be an electrolytic or an electrolessprocess (i.e. electro- or electroless deposition.) After forming thebioactive composite structure, the bioactive compositestructure/substrate combination is removed from the bath containing theelectrochemical solution.

After removing the bioactive composite structure/substrate combinationfrom the bath, the combination may be further processed if desired. Forexample, in some embodiments, a topcoat may be formed on the bioactivecomposite structure. Additional details about the topcoat and othersubsequent processing steps are described below.

A device including a bioactive composite structure according to anembodiment of the invention is shown in FIGS. 1 and 2. The Figuresdepict a device 100 including a bioactive composite structure 101including a metal matrix 10 and the bioactive material 14 within themetal matrix 10. The bioactive composite structure 101 is on a substrate12. The proportion of bioactive material to the proportion of metal in abioactive composite structure is high relative to the proportions ofbioactive material that might be found in conventional bioactivecomposite structures, containing a metallic matrix.

Embodiments of the invention have a number of other advantages overconventional methods for forming bioactive composite structures. First,when bioactive materials are incorporated into a metallic matrix usingan electrochemical process, the electrochemical process does not damagethe bioactive material. Unlike high temperature processes for formingmetallic matrices (e.g., sintering), embodiments of the invention can beperformed at temperatures that do not harm bioactive materials (e.g.,proteins). Second, in some embodiments of the invention, bioactivematerials are more easily loaded into a metallic matrix than inconventional metallic matrices. For example, problems associated withimpregnating a preformed metallic matrix with a solution comprising acarrier and a bioactive material are generally not present inembodiments of the invention. Consequently, the bioactive compositestructures according to embodiments of the invention can have higherproportions of bioactive materials than conventional bioactive compositestructures. Third, in some embodiments, the formed bioactive compositestructure releases a bioactive material in a very localized area atspecified times in an active and/or passive fashion over a period ofmonths to years. The controlled and/or predictable release of thebioactive material can be achieved using embodiments of the invention.Fourth, when the bioactive composite material is in the form of a layeron a metallic substrate, the bioactive composite material and themetallic substrate can have similar properties. For example, theductility and the modulae of elasticity of the bioactive compositematerial can be substantially the same as the underlying substrate. Inanother example, the metallic matrix of the bioactive compositestructure and the substrate can both be metallic in embodiments of theinvention. They can have similar thermal expansion coefficients, thusdecreasing the likelihood that the two materials may separate due tothermal expansion differences. Fifth, the bioactive composite structurescan be made uniform in composition and thickness in embodiments of theinvention. If the bioactive composite structure is in the form of alayer on a metallic substrate with a complex shape, the layer can easilyconform to the complex shape. Other advantages of embodiments of theinvention are provided below.

A. Substrate Preparation

Any suitable substrate may be coated using embodiments of the invention.The substrate may be porous or solid, and may have a planar ornon-planar surface (e.g., curved). The substrate could also be flexibleor rigid. In some embodiments, the substrate may be a stent body, animplant body, a particle, a pellet, an electrode, etc.

The substrate may comprise any suitable material. For instance, thesubstrate may comprise a metal, ceramic, polymeric material, or acomposite material. Illustratively, the substrate may comprise a metalsuch as stainless steel or nitinol (Ni-Ti alloy). Alternatively, thesubstrate may comprise a polymeric material including fluoropolymerssuch as polytetrafluoroethylene. In some embodiments, the substrate maycomprise a sacrificial material. A sacrificial material is one that canbe removed, for example, by etching, thereafter leaving a free-standingbioactive composite structure.

The substrate may be prepared in any suitable manner prior to forming abioactive composite structure on it. For example, the substrate surfacemay be sensitized and/or catalyzed prior to performing an electrolessdeposition process (if the surface of the substrate is not itselfautocatalytic). Metals such as Sn can be used as sensitizing agents.Many metals (e.g., Ni, Co, Cu, Ag, Au, Pd, Pt) are good auto catalysts.Palladium (Pd), platinum (Pt), and copper (Cu) are examples of“universal” nucleation center forming catalysts. In addition, manynon-metals are good catalysts as well.

Before forming the bioactive composite structure, the substrate may alsobe rinsed and/or precleaned if desired. Any suitable rinsing orpre-cleaning liquid or gas could be used to remove impurities from thesurface of the substrate before performing the electrochemical process.Also, in some embodiments involving electroless deposition, distilledwater may be used to rinse the substrate after sensitizing and/orcatalyzing, but before performing the electrochemical process in orderto remove loosely attached molecules of the sensitizer and/or catalyst.In addition to, or in place of this, an anodic, or sometimes cathodic,cleaning process is used in some embodiments to produce pits whichenhance adhesion.

B. Electrochemical Processes

In embodiments of the invention, an electrochemical deposition processis used to form the bioactive composite structure. Electrochemicaldeposition processes include electrolytic (electro) deposition andelectroless deposition.

In embodiments of the invention, a bioactive material is incorporatedinto an electrochemical bath along with a source for metal ions. Thebioactive material can include any of the particular materials mentionedabove as well as other materials. For example, the bioactive materialrefers to any organic, inorganic, or living agent that is biologicallyactive or relevant. The bioactive material could also comprisebiologically active molecules such as drugs. In embodiments of theinvention, the bioactive material may be soluble or insoluble in theelectrochemical solution.

The bioactive material may also comprise particles (e.g., in the sizerange of 0.1 to about 10 microns). The particles may comprise thebioactive material in a crystallized form. Alternatively, the particlescomprise a polymer, ceramic, or metal, which can store a bioactivematerial. The particles are preferably insoluble in the electrochemicalsolution. In this case, a particulate stabilizer such as a surfactantcould be added to the electrochemical solution to improve thehomogeneity of the particles in the solution.

Without being bound by theory, it is believed that when performing anelectrochemical deposition process according to some embodiments,nanometer-sized crystallites (crystallized metal atoms) and thebioactive material “co-deposit”. At first, the process occurs on thesurface of the substrate. Following the deposition of tens of nanometersof metal, the co-deposition occurs on the already deposited metal. Thus,the bioactive material and the metal atoms may deposit substantiallysimultaneously. When co-depositing metal atoms and the bioactivematerial, the bioactive material is incorporated into the metal matrix.These crystallites confine the bioactive material in the formedbioactive composite structure.

By co-depositing the bioactive material along with the metal, theconcentration of the bioactive material in the bioactive compositestructure is high. Moreover, the problems associated with impregnatingporous structures with bioactive materials are not present inembodiments of the invention. In embodiments of the invention, thebioactive material substantially fills the voids in the metal matrix sothat the loading of the bioactive material in the metal matrix ismaximized.

As noted, electrochemical processes include electrolytic (electro) andelectroless deposition processes. In electrolytic (electro) deposition,an anode and cathode are electrically coupled through an electrolyte. Ascurrent passes between the electrodes, metal is deposited on the cathodewhile it is either dissolved from the anode or originates from theelectrolyte solution. Electrolytic deposition processes are well knownin, for example, the metal plating industry and in the electronicsindustry.

An exemplary reaction sequence for the reduction of metal in anelectrodeposition process is as follows:M ^(Z+)solution+ze→M _(lattice (electrode))

In this equation, M is a metal atom, M^(z+) is a metal ion with z chargeunits and e is an electron (carrying a unit charge). The reaction at thecathode is a (reduction) reaction and is the location whereelectrodeposition occurs. There is also an anode where oxidation takesplace. To complete the circuit, an electrolyte solution is provided. Theoxidation and reduction reactions occur in separate locations in thesolution. In an electrolytic process, the substrate is a conductor as itserves as the cathode in the process. Specific electrolytic depositionconditions such as the current density, metal ion concentration, andbioactive material concentration can be determined by those of ordinaryskill in the art.

Electroless deposition processes can also be used to form a bioactivecomposite structure. In an electroless deposition process, current doesnot pass through the solution. Rather, the oxidation and reductionprocesses both occur at the same “electrode” (i.e., on the substrate).It is for this reason that electroless deposition results in thedeposition of a metal and an anodic product (e.g., nickel and nickel-phosphorus).

In an electroless deposition process, the fundamental reaction is:M ^(z+)solution+R _(ed solution) >M _(lattice(catalytic surface)) +Ox_(solution)

In this equation, R is a reducing agent, which passes electrons to thesubstrate and the metal ions. Ox is the oxidized byproduct of thereaction. In an electroless process, electron transfer occurs atsubstrate reaction sites (initially the nucleation sites on thesubstrate; these then form into sites that are tens of nanometers insize). The reaction is first catalyzed by the substrate and issubsequently auto-catalyzed by the reduced metal as a metal matrixforms.

The electroless deposition solution can comprise metal ions and abioactive material. Suitable bioactive materials are described above.The solvent that is used in the electroless deposition solution mayinclude water so that the deposition solution is aqueous. Depositionconditions such as the pH, deposition time, bath constituents, anddeposition temperature may be chosen by those of ordinary skill in theart.

Any suitable source of metal ions may be used in embodiments of theinvention. The metal ions in the electrochemical solution can be derivedfrom soluble metal salts before they are in the electrochemicalsolution. In solution, the ions forming the metal salts may dissociatefrom each other. Examples of suitable metal salts for nickel ionsinclude nickel sulfate, nickel chloride, and nickel sulfamate. Examplesof suitable metal salts for copper ions include cupric and cuprous saltssuch as cuprous chloride or sulfate. Examples of suitable metal saltsfor tin cations may include stannous chloride or stannous floroborate.Other suitable salts useful for depositing other metals are known in theelectroless deposition art. Different types of salts can be used if ametal alloy matrix is to be formed.

The electrochemical solution may also include a reducing agent,complexing agents, stablizers, and buffers. The reducing agent reducesthe oxidation state of the metal ions in solution so that the metal ionsdeposit on the surface of the substrate as metal. Exemplary reducingcompounds include boron compounds such as amine borane and phosphitessuch as sodium hypophosphite. Complexing agents are used to hold themetal in solution. Buffers and stabilizers are used to increase bathlife and improve the stability of the bath. Buffers are used to controlthe pH of the electrochemical solution. Stabilizers can be used to keepthe solution homogeneous. Exemplary stabilizers include lead, cadmium,copper ions, etc. Reducers, complexing agents, stabilizers and buffersare well known in the electroless deposition art and can be chosen bythose of ordinary skill in the art.

Illustratively, a nickel-phosphorous alloy matrix can be electrolesslydeposited on a substrate along with a bioactive material such as a drug.The substrate may need to be activated and/or catalyzed (using, e.g., bySn and/or Pd) prior to metallizing. To produce this alloy matrix, atypical electroless deposition solution contains NiSO₄ (26 g/L), NaH₂PO₂(26 g/L), Na-acetate (34 g/L) and malic acid (21 g/L). The solution maybe in the form of a bath and may contain ions derived from thepreviously mentioned salts. A bioactive material is also in the bath. Inthis example, sodium hypophosphite is the reducing agent and nickel ionsare reduced by the sodium hypophosphite. The temperature of the bath isfrom room temperature to 95° C. depending on desired plating time. ThepH is generally from about 5 to about 7 (these processing conditionscould be used in other embodiments). The substrate to be coated is thenimmersed in the solution and a bioactive composite structure can beformed on the substrate after a predetermined amount of time. The Niions in solution deposit onto the substrate as pure nickel (reductionreaction) along with nickel-phosphorous alloy (oxidation reaction); thebioactive material co-deposits along the crystallite and grainboundaries of the deposited metal matrix to form a bioactive compositestructure. The bioactive material may co-deposit along with nickelatoms. Typically, the amount of phosphorous ranges from <1% to >25%(mole %) and can be varied by techniques known to those skilled in theart.

Although co-deposition of the metal atoms and the bioactive material ispreferred, co-deposition is not necessary in some embodiments. Forexample, in other embodiments, a very thin metallic layer on the orderof tens of nanometers can be formed on a substrate. A bioactive materialis then either adsorbed, covalently bound, or deposited on top of thenanometer thick metallic layer. Additional metallic layers aresubsequently added afterward. In between metallic layers, additionallayers of bioactive material can be adsorbed, covalently bound, ordeposited. This type of process produces a dense bioactive compositematerial.

The metallic matrix of the bioactive composite structure can include anysuitable metal. The metal in the metallic matrix may be the same as ordifferent from the substrate metal (if the substrate is metallic). Themetallic matrix may include, for example, noble metals or transitionmetals. Suitable metals include nickel, copper, cobalt, palladium,platinum, chromium, iron, gold, and silver and alloys thereof. Examplesof suitable nickel-based alloys include Ni—Cr, Ni—P, and Ni—B. Any ofthese or other metallic materials may be deposited using a suitableelectrochemical process. Appropriate metal salts can be selected toprovide appropriate metal ions in the electrochemical solution for themetal matrix that is to be formed.

The metallic matrix may also have voids in a crystal lattice. Typically,the average void size is less than about 1 micron. For example, in someembodiments, the average size of the voids in the metallic matrix may beless than about 100 angstroms (e.g., less than about 10 nanometers). Thebioactive material can be incorporated into the voids of the metallicmatrix.

In the formed bioactive composite material, the volume percent of thebioactive material is high. For example, in embodiments of theinvention, the bioactive material can make up percentage of thebioactive composite structure. Preferably, the bioactive material canmake up greater than about 10%, or greater than about 25% percent byvolume of the bioactive material.

The bioactive composite structure may be in any suitable form. Forexample, the bioactive composite material may in the form of a layer onthe substrate. The layer may have any suitable thickness. For example,the layer may have a thickness of less than about 100 microns in someembodiments (e.g., from about 0.5 to about 10 microns). In anotherexample, the layer may have a thickness of greater than about 1 mm. Inother embodiments, the bioactive composite structure need not be in theform of a layer. For example, the bioactive composite structure could bein the form of small particles in some embodiments.

Forming a bioactive composite structure using an electroless depositionprocess is advantageous. First, by using an electroless depositionprocess, the size of the crystallites and consequent percentage ofbioactive material is controllable. Parameters such as the pH,temperature, and the constituents of the deposition bath can be adjustedby the person of ordinary skill in the art to alter the volumepercentage of bioactive material in the formed metallic matrix. Second,using an electroless process, substrates having complex geometries canbe evenly coated with a bioactive composite structure. As the solutionsare aqueous in nature, viscous effects do not dominate in an electrolessdeposition process (as compared to coating polymeric substances whichare viscous). Third, in an electroless deposition process, depositionconditions are mild, occurring at or near room temperature and at ornear body physiologic pH. Bioactive materials are not damaged in theprocess of forming the bioactive composite material. Fourth, the methodsaccording to embodiments of the invention are economical and scaleable,and are more cost-effective than other methods of forming bioactivecomposite structures.

C. Subsequent Processing

After the bioactive composite structure is formed, it may optionally befurther processed in any suitable manner. For example, in someembodiments, a topcoat is formed on top of a bioactive compositestructure. FIG. 3 illustrates a device 100 including a bioactivecomposite structure 10 in the form of a layer in between a substrate 12and a topcoat 20.

The topcoat can include any suitable material and may be in any suitableform. It can be amorphous or crystalline, and may include a metal,polymer, ceramic, etc. The topcoat may also be porous or solid(continuous).

The topcoat can be deposited using any suitable process. For example,the above-described processes (e.g., electro- and electrolessdeposition) could be used to form the topcoat or another process may beused to form the topcoat. Alternatively, the topcoat could be formed byprocesses such as dip coating, spray coating, vapor deposition, etc.

The thickness of the topcoat may vary in embodiments of the invention.For example, in some embodiments, the topcoat may have a thicknessgreater than about 100 microns. Of course, the thickness of the topcoatcan depend on the end use for the device being formed.

In embodiments of the invention, the topcoat may be the only layer onthe bioactive composite structure. In other embodiments, any number ofsuitable topcoat layers may be added to the bioactive compositestructure. For example, it is possible that tens to hundreds ofindividual layers could be formed on the bioactive composite structure(some or all of these layers may be bioactive).

In some embodiments, the topcoat can improve the properties of thebioactive composite structure. For example, the topcoat may include amembrane (e.g., collagen type 4) that is covalently bound to thebioactive composite structure. The topcoat's function can be to induceendothelial attachment to the surface of the bioactive compositestructure, while the bioactive material in the bioactive compositestructure diffuses from below the topcoat. In another embodiment, agrowth factor such as endothelial growth factor (EGF) or vascularendothelial growth factor (VEGF) is present in a topcoat that is on thebioactive composite structure. The growth factor is released from thetopcoat to induce endothelial growth while the bioactive compositestructure releases an inhibitor of smooth muscle cell growth.

In yet other embodiments, the topcoat can improve the radio-opacity of amedical device which includes the bioactive composite structure, whilethe underlying bioactive composite structure releases molecules toperform another function. For example, drugs can be released from thebioactive composite structure to prevent smooth muscle cell overgrowth,while a topcoat on the bioactive composite structure improves theradio-opacity of the formed medical device. Illustratively, a topcoatcomprising Ni-Cr (nickel chromium) and/or gold can be deposited on topof a bioactive composite structure comprising Ni—P to enhance theradio-opacity of a device incorporating the bioactive compositestructure. Underneath the topcoat, a smooth muscle cell inhibitor suchas sirolimus is released over a 30-60 day time period from the bioactivecomposite structure

The topcoat can also be used to alter the release kinetics of thebioactive material in the underlying bioactive composite structure. Forexample, an electroless nickel-chrome, nickel-phosphorous, orcobalt-chrome coating without bioactive material can serve as a topcoat.This would require the bioactive material to travel through anadditional layer of material before entering the surroundingenvironment, thereby delaying the release of bioactive material. Therelease kinetics of the formed medical device can be adjusted in thismanner.

Alternatively, the topcoat comprises a polymeric material (or othermaterial). In this case, a bioactive material that is the same ordifferent than the bioactive material in the bioactive compositestructure may be included in the topcoat. For example, when the topcoatcomprises a polymeric storage and release medium, the bioactive materialtherein can release quickly (e.g., days) from the topcoat, while thematerial in the bioactive composite structure is released over a periodof months to years. In this embodiment, the medical device that isformed may include the combination of a topcoat comprising a polymericstorage and release medium, and a metallic storage and release medium.

Suitable polymers in the topcoat are preferably biocompatible (i.e.,they do not elicit any negative tissue reaction) and can be degradable.Such polymers may include lactone-based polyesters or copolyesters, forexample, polylactide, polycaprolacton-glycolide, polyorthoesters,polyanhydrides; poly-aminoacids; polysaccharides; polyphosphazenes; andpoly (ether-ester) copolymers.

Nonabsorbable biocompatible polymers may also be used in the topcoat.Such polymers may include, for example, polydimethylsiloxane;poly(ethylene-vinylacetate); acrylate based polymers or copolymers,e.g., poly(hydroxyethyl methylmethacrylate); fluorinated polymers suchas polytetrafluoroethylene; and cellulose esters.

In yet other embodiments, the topcoat that is on the bioactive compositestructure can be a self-assembled monolayer (SAM). The thickness of theself-assembled monolayer may be less than 1 nanometer (i.e., a molecularmonolayer) in some embodiments. In one example, a thiol based monolayercan be adsorbed on a nickel matrix of a bioactive composite structurethrough the thiol functional group and can self-assemble on the nickelmatrix. The introduction of the self-assembled monolayer can permitdifferent surface ligands to be used with the bioactive compositestructure. That is, various ligands or moieties can be attached to theends of the molecules in the monolayer that extend away from thebioactive composite structure.

In another embodiment, after forming the bioactive composite structureon a substrate, the substrate can be removed. This could be done toelectroform a free-standing bioactive composite structure. For example,as noted above, when forming a medical device, a bioactive compositestructure can be formed on a substrate. However, instead of leaving thesubstrate in the final medical device, the substrate may be etched toremove it from the formed bioactive composite structure. For example,the substrate may comprise an etchable material. Etchable materialsinclude metals such as aluminum or copper or polymeric substances.

The substrate is a sacrificial substrate and can be used as a mandrelfor forming a free-standing bioactive composite structure. After etchingthe substrate, a free-standing bioactive composite structure is formed.Stents, for example, can be formed in this manner. Details regarding theformation of stents using sacrificial substrates are found in U.S. Pat.No. 6,019,784. This U.S. Patent is herein incorporated by reference inits entirety.

The free-standing bioactive composite structure may have dimension onthe order of nanometers (e.g., nanoparticles) to meters. For example,the thickness of the free-standing bioactive composite structure may beless than about 1 mm thick. As in other embodiments, a topcoat could beformed on a free-standing bioactive composite structure.

III. Releasing Bioactive Material From a Bioactive Composite Structure

The bioactive composite structures according to embodiments of theinvention can be present in medical devices that are used in vivo. Theycan be implanted in the body of a patient when used, or could be usedexternal to the body of a patient. In such medical devices, the longterm release of a bioactive material from the bioactive compositematerial is desirable in some instances.

In some embodiments, the bioactive material can diffuse from themetallic matrix in the bioactive composite structure. FIGS. 6 and 7(described in further detail below) show the results of experimentsusing embodiments of the invention. As shown in FIGS. 6 and 7, inembodiments of the invention, drugs can be released over long periods oftime (e.g., greater than about 10 or about 20 days). Again, withoutbeing bound by theory, the release mechanisms in the examples shown inFIGS. 6 and 7 are indicative of simple diffusion. The bioactive materialdiffuses through the metallic matrix, that is, between individualcrystallites and grain boundaries. The bioactive material exchangesplaces with the components of the metallic film and then diffuses intoliquid at the interface of the metallic film and liquid.

Alternatively, the metallic matrix of the bioactive composite structurecan erode to release the bioactive material in it. For example, themetallic matrix can be susceptible to electrolytic corrosion. Themetallic matrix of the bioactive composite structure can serve as ananode, which results in corrosion of the metallic matrix when current ispassed through a circuit which includes the composite structure as ananode. As a result of the corrosion process, the bioactive material isliberated from the metallic matrix. This is useful both in vivo and invitro. By using a corrosion process, small, controllable quantities of abioactive material (e.g., a drug or DNA) can be released in a highlylocalized regions at specified times within a patient or within adiagnostic assay.

Corrosion can occur actively or passively. In an active corrosionprocess, current is actively applied to the bioactive compositestructure using an external power source to corrode the metallic matrix.In a passive corrosion process, the oxidation of the matrix metal of thebioactive composite material can be caused by the difference between theelectrical potential of the metallic matrix and an adjacent metal orsolution. For example, galvanic corrosion is caused when two metalpieces, in electrical contact with each other, or two adjacent metalareas are at different electrochemical potential. The two metal partswill constitute a galvanic cell, in which the metal part with the lowestelectrochemical potential (i.e., the more active metal) will corrode.

In another embodiment, mechanical energy such as ultrasonic energy isapplied to the bioactive composite structure. The mechanical energyhastens the rate of diffusion of the bioactive material from thebioactive composite structure. In this embodiment, the metallic matrixmay or may not erode. In the case of a stent or other implanted medicaldevice, ultrasonic energy may be applied non-invasively to a patient sothat the release of the bioactive material from the stent can occur at adesired time. For example, the application of ultrasonic energy can be,for instance, days, weeks, or months after the stent is implanted.

IV. Medical Devices

Embodiments of the invention include any suitable medical deviceincorporating the bioactive composite structure. For example, medicaldevices according to embodiments of the invention include stents,orthopedic implants, cardiovascular implants, electrodes, sensors, drugdelivery capsules, surgical clips, micromechanical systems, andnanomechanical systems. A schematic drawing of a stent 150 in an arteryis shown in FIGS. 4(a)-4(c).

In other embodiments, the bioactive composite structures are applied toblood or tissue contacting medical devices, which are dependent onendothelialization of the implant surfaces for biocompatibility. Thesedevices include ventricular assist devices (VADs), total artificialhearts (TAHs), and heart valves. In comparison to stents, which havediscontinuous surfaces (e.g., wire meshes with windows), these deviceshave continuous surfaces. They rely on cell seeding from thebloodstream. Accordingly, the bioactive composite structures cancomprise growth factors. The bioactive composite structures provide anattachment surface that could facilitate the attachment and subsequentgrowth processes of endothelial cells on the surface. Such growthfactors include any of a host of integrins, selectins, growth factors,and peptides, which can assist and hasten cell migration and adhesion.

The bioactive composite structures could also be used in drug releasedevices such as ingestible pills or devices capable of traveling in thebloodstream. These devices can take the form of a sphere, square orcylinder of sufficient size to fit into a body cavity. They can beplaced in the human body transcutaneously or orally. Subsequent releaseoccurs from the metallic matrix by one of the methods described above.This type of drug storage and delivery system can be produced incombination with other delivery vehicles such as biodegradeablepolymers.

In another embodiment, the bioactive composite material may be presentin wells or channels in a microchip-type device. The bioactive compositematerial in the wells or channels can be covered with a topcoat that iserodable. For example, the metallic matrix of the bioactive compositestructure may comprise nickel or a nickel alloy, while the topcoatcomprises gold. Electrical current is selectively applied to the goldtopcoat, thereby causing it to erode. As a result of the erosionprocess, the bioactive material is free to diffuse out of each well orchannel. Alternatively, the release of bioactive material from each wellor channel can be induced by an electrical current. Passive corrosioncan be induced by a bimetallic EMF (electromotive force) created by thecombination of two metals. Active release can be induced by currentinduced erosion of the metallic matrix. In both cases, the amount ofcurrent applied to the metallic matrix can be directly proportion to theamount of released bioactive material. This design reduces thecomplexity of such systems compared to current designs.

Aside from use in therapeutic medical devices, the bioactive compositestructure can be used in diagnostic devices and bioassays where aprecise quantity of bioactive material is required in a spatially and/ortemporally controlled fashion. They can be used in the drug discoveryprocess. Bioassays for drug discovery are increasing in complexity andin many cases utilize live cells for bioassays. Modern surfacetechnologies make it possible to study the effects of local chemicalgradients in the study of cell response as well as local environmentalalterations in cell culture, such as pH. Utilizing embodiments of theinvention, dynamic release of bioactive materials at specific places atspecific times and in controlled quantities could be used in diagnosticdevices and bioassays.

In one embodiment, a bioactive composite structure is formed underneaththe surface on which cells are cultured. The bioactive compositestructure can be in the form of a pattern with varying concentrations ofbioactive materials or in a layer containing one concentration ofmolecule. When appropriate, the matrix of the bioactive compositestructure is dissolved via electrolytic corrosion and the bioactivematerial is released almost instantaneously into the environmentsurrounding the cells of interest. The amount of applied currentdetermines the amount of bioactive material released.

This type of technology is meant to mimic the in vivo environment andcan be used to study the molecular effects of specific molecules oncells at specific times identified with other biological assays. Forexample, the affect of molecule X on the cell cycle during G1 or G2,etc. where G1 and G2 are measured with a well-known assay such as afluorescence assay.

EXAMPLE I

Six bioactive composite structures were formed. Each bioactive compositestructure comprised a nickel-phosphorous metallic matrix formed on ametallic substrate using an electroless deposition process. Thesubstrates used were foils. Three substrates comprised medical grade316L stainless steel and three substrates comprised nitinol.fluorouracil, tetracycline, and albumin were respectively co-depositedwith the nickel-phosphorous on the stainless steel and nitinolsubstrates.

Each substrate was first prepared using process steps show in FIG. 4.First, the surface of the substrate is cleaned (step 32). Then, thesubstrate surface is rinsed with distilled water (step 34). Afterrinsing, the surface of a substrate is sensitized with Sn(II) (step 36).A solution of 0.1 g/L of stannous chloride may be used as a sensitizingsolution. After depositing Sn(II) on the surface of the substrate, thesubstrate is again rinsed with distilled water (step 38) in a secondrinse step. Then, a Pd (II) catalyst is deposited on the surface of thesubstrate. A solution of 0.1 g/L palladium chloride may be used as acatalyzing solution (step 40). The surface of the substrate is againrinsed in a third rinsing step (step 42). Distilled water may be used asthe rinsing fluid. After the third rinsing step, the substrate iscatalyzed and is ready for electroless deposition. Three stainless steeland three nitinol substrates were prepared using the above describedcatalyzing process.

Three different electroless plating baths were made. The three differentbaths were the same, except that the bioactive material was different ineach bath. Bath 1 contained 5-fluorouracil, Bath 2 containedtetracycline, and Bath 3 contained albumin. Each bath was at ambientpressure, at a pH of about 7, and at a temperature of about 40° C. TABLE1 Ingredient Concentration Nickel Sulfamate   29 g/L SodiumHypophosphite   17 g/L Sodium Succinate   15 g/L Succinic Acid  1.3 g/LBioactive material: 0.25 g/L (Bath 1), 0.25 g/L 5-fluorouracil (Bath 1),(Bath 2), and 100 ug/ml tetracycline (Bath 2), and (Bath 3) albumin(Bath 3).

Six bioactive composite structures in the form of layers wererespectively formed on the substrates (3 stainless steel substrates and3 nitinol substrates) using electroless deposition (step 44). Ingeneral, the time in the bath determines the thickness of the bioactivecomposite structure. Each substrate was immersed in a bath for about 10minutes to yield a layer about 4 microns thick. The concentration of thebioactive material in the bath determines the concentration of thebioactive material in the coating. For example, when albumin was used asa bioactive material, the concentration in the coating was 1:10 w/walbumin:metal with 100 ug/ml concentration of albumin in the startingbath.

For each bioactive composite structure, the weight proportion of thebioactive material to the metallic matrix material is listed in Table 2.

The weight proportions of the bioactive materials to the metallicmatrices for each bioactive composite material were determined asfollows. For each bioactive composite structure/substrate combination,pre- and post-deposition dry weights were measured. After they wereformed, each bioactive composite structure/substrate combination wasthen placed in an electrolytic bath, with the bioactive compositestructure being made the anode of an electrolytic circuit. With currentintroduced into the bath, the metallic matrix of the bioactive compositestructure was corroded and passed from the substrate into theelectrolytic bath. The amount of the bioactive material in the bath wasthen optically measured with the use of a spectrophotometer. The numbersbelow in Table 2 represent the weight_(x)/weight _(Ni-p), wherein the xrepresents the bioactive material and Ni—P is the electrochemicallydeposited metal matrix. As shown by the results in Table 2, theconcentration of bioactive material to metal is high in each case. TABLE2 W/W concentration of bioactive material to Deposited Ni-P Matrix onNitinol and 316L Substrates Fluorouracil Tetracycline Albumin Nitinol0.100 mg/3 mg 0.3 mg/4 mg 0.5 mg/4.8 mg 316L Stainless  0.4 mg/3 mg 0.5mg/4 mg 0.4 mg/4 mg   Steel

EXAMPLE 2

Coated stents were formed using the same basic electroless depositionprocedure in Example 1. However, in this example, instead of foilsubstrates, Johnson and Johnson Bx velocity stents (stainless steel) andJohnson and Johnson Smart stents (nitinol) were used as substrates.Bioactive composite structures in the form of layers were formed on thestents.

FIG. 6 shows a graph of the drug elution profiles when Johnson andJohnson Bx Velocity stents (316L stainless steel) were used assubstrates. FIG. 7 shows a graph of the drug elution profiles whenJohnson and Johnson Smart stents (nitinol) were used as substrates. Theamounts on the y-axis of the graphs represent the amount of bioactivematerial remaining on the stent after elution into a physiologic salinesolution.

A similar anodization process as was used in the stent examples as wasagain applied to the foil substrates. After coating, the coated stentwas placed in a physiologic saline solution and the solution changeddaily. On the indicated days, the stent coatings were anodized. Theamount of bioactive material released in each case was determined usinga spectrophotometric assay.

As can be seen in FIGS. 6 and 7, molecules are released from embodimentsof the invention over long periods of time. Appreciable amounts of drugssuch as fluorouracil, albumin, and tetracycline were released over 40days. No appreciable corrosion of the coating was observed.

EXAMPLE 3

Additional experiments were performed in order to further demonstratethe wide range of bioactive materials which can be stored and releasedin the coating. Table 3 depicts several experiments following thegeneral procedures outlined in example 1, each with one time point andfor a new bioactive material. ΔA is the difference in absorbance betweenan elution bath from the sample containing the respective bioactivematerial and the absorbance from a sample with pure coating (i.e.control). In this instance, a 1 cm² medical grade 316L stainless steelsample was coated using the above mentioned process. In addition totetracycline (an antibiotic), Fluorouracil (an antimetabolite), andalbumin (a large protein), these experiments depict the ability to storeand release rapamycin (a highly lipophilic antirestenosis compound),heparin (a highly hydrophilic, large carbohydrate, anticoagulantmolecule), and hydrocortisone (a lipophilic, anti-inflammatorycompound).

Table 3 shows the optical absorbance from an elution bath immediatelyafter deposition and after seven days in a 0.9% saline solution. ΔArefers to the absorbance difference between coated with bioactivematerial and coated without bioactive material. The number inparentheses refers to the characteristic absorbance for each material.TABLE 3 Time = 0, ΔA Time = 0, 7 days, ΔA Rapamycin 0 1.85 (274 nm)Heparin 0  2.4 (230 nm) Hydrocortisone 0  1.2 (250 nm)

EXAMPLE 4

The following is a topcoat example. After applying a bioactive coatingto a sample of Nitinol (commercially available from Nitinol Devices andComponents, Inc), as outlined in example 1, the sample is furtherprocessed by placing it in the cathodic position in a second bathcontaining 100 g/L chromic acid (CrO₃) and 1 g/l H₂SO₄. 200-300 mA/cm²is applied to the sample for about 10 to about 20 seconds to produce atopcoat which delays the diffusion of bioactive material. The chromiumtopcoat also augments the radiopacity of the device. Under theseconditions, release of bioactive material is delayed several days toweeks.

EXAMPLE 5

Various of the embodiments of the invention, such as according tospecific aspects provided above, provide valuable use in coating medicaldevices notwithstanding the presence or absence of bioactive agents ormaterials in the coating, and therefore are to be considered broadlybeneficial aspects of the invention.

One particular such aspect is illustrated by the following example,wherein nickel release from nickel-titanium alloy is reduced by use ofan illustrative coating embodiment of the invention usingnickel-phosphorous coating solution and process without bioactive agent.

In a separate experiment, a 1 cm² sample of nickel-titanium alloy wasanodized to completely remove the heavy oxide layer on its surfaceexposing pure nickel titanium. The substrate was subsequently placedinto an electroless nickel bath (Bath 1) without a bioactive material. Atremendous autocatalytic reaction was noted on the surface of thenitinol. After 30 seconds, the nickel-titanium substrate was removedfrom the bath and a shiny coating noted. This coating was not removableby scratching or with scotch tape and showed superior adherence to thenitinol substrate.

The new nickel-phosphorous coated nickel-titanium sample (Ni—P—NiTi)coating was then placed into 1.5 ml 0.9% sodium chloride solution andincubated at 37 degrees for 96 hours after which the sodium chloridesolution was removed and replaced with another 1.5 ml and incubated foran additional 96 hours. A parallel control sample of “as-received”nitinol (NiTi) was also incubated at 37 degrees for 96 hours and 192hours. Atomic Absorption Spectroscopy was used to analyze the nickelcontent contained in the solution in which the samples were incubated.Results are as follows in parts per million (ppm): Ni-P-NiTi (ppm) NiTi(ppm) Nickel released 96 hours 15.6 19.6 Nickel released 192 .6 1.2hours

It can be seen that the sample coated with nickel phosphorous resultedin a 25% decrease in the nickel which leached from the nickel-titaniumsubstrate after 96 hours and a 50% decrease in the subsequent 96 hours,both when compared to the uncoated control sample of nickel-titaniumsubstrate.

This benefit derived from coating a nickel-titanium sample according tothe invention is exemplary of various broadly beneficial aspects of theinvention. In one regard, a substrate comprising nickel is modified torelease less nickel than it otherwise would without being treatedaccording to the invention. This is valuable across a wide range ofmedical devices, in particular implants, which otherwise suffer fromnickel release concerns for biocompatibility reasons, in particularregarding patient populations who have nickel allergies. Examples ofsuch medical devices where the present invention provides such value,without requiring incorporation of bioactive agents (or with suchagents, if also desired) includes for example all nickel-titaniummedical devices, such as according to further illustrative examplesstents, filters, wires, or orthodontic devices.

Moreover, the ability to use the same coating and coating process to (a)inhibit release of nickel from such substrates, (b) also provide forcoating of bioactive agents, and (c) increase the radio-opacity of theunderlying substrate, or any combination thereof, e.g. (a) and (b), (a)and (c), or (b) and (c), is a highly beneficial combination madepossible according to the present invention and should be considered anindependent, broad aspect of the invention.

Other benefits are apparent according to use of the present invention,with or without inclusion of bioactive agents in a sample formed orcoated according to electroless electrochemical deposition processaccording to the present embodiments. In one particular example, variousformulations of coatings and their related processes may be used toenhance the radiopacity of a substrate medical device. Morespecifically, preparations using relatively radiopaque materials such aschromium for example, e.g. cobalt-chromium combinations, will tend toenhance radiopacity of substrate materials that are relatively lessradiopaque, such as for example nickel-titanium alloy substrates, orsubstrates containing similar radiopaque material(s) but in less denseand therefore less radiopaque proportions. Therefore, coating processesand resulting coated samples having radiopacity enhanced by a coatingaccording to the present embodiments are considered independentlybeneficial aspects of the invention, with or without inclusion ofbioactive agents, and with or without the result of enhancedbiocompatibility (e.g. reduced nickel release), though such combinationsapparent to one of ordinary skill provide significant further benefit.

Various particular embodiments have been herein described for thepurpose of illustrating certain highly beneficial aspects of the presentinvention. However, many such specific embodiments, despite theirspecific benefits, should not be considered limiting in all cases and inmany regards are exemplary of broader aspects of the invention. Forexample, specific examples of experiments are herein shown with respectto particular coating processes and results, but other suitable coatingformulations, bioactive agents, or the like may be substituted for thespecific embodiments described without departing from the intended scopeof the invention.

More specifically, nickel-phosphorous coating preparations have beengenerally used in the experiments recited in the examples to illustrateparticular beneficial results. However, other suitable substitutematerials may be used in such preparations and still achieve various ofthe objectives and broad aspects of the invention, such as for examplepreparations including: one of nickel or phosphorous with suitablesubstitutes for the other; cobalt; boron; chromium; or other suitablecombinations, alloys, or blends of such materials as herein described.Accordingly, the specific combination solutions of nickel-phosphorous isillustrative of broader aspects of the invention encompassing theseother substitutes, such as in certain regards to solutions or structuresrelated to: use of metals or other materials forming positive valenceions and reducing agents thereof (e.g. reducing agents of metals);cations and anions; combinations of positive and negative bivalent ortrivalent materials; solutions adapted to exhibit electrolesselectrochemical deposition onto substrates; sterilized structures thatare electroless electrochemically formed or coated; etc. These broadaspects illustrated by use of the nickel-phosphorous electrochemicaldeposition process of the examples include combinations with or withoutthe bioactive agents as either specifically herein described or suitablecombinations, blends, or substitutes thereof

In another regard, where particular bioactive agents are specified andused in the experiments of the Examples, these are intended to beillustrative of other compounds of similar characteristics (though thespecific agents are related methods and structures are considered ofhigh independent value). For example, tetracycline may in one regard becharacterized as an antibiotic agent with respect to certain foreignorganisms, and is further characterized as a bioactive agent that isanti-proliferative when it is inhibiting autogenous cell growth, andtherefore a possible suitable substitute as an anti-restenosis agent. Inanother example, 5-fluorouracil is characterized as an mitotic inhibitoras it interferes with DNA replication, mitosis, and cell growth; it isfurther characterized as being illustrative of the following types ofbioactive agents: fluorouracils; uracil analogues; and anti-restenosisagents. Albumin is another compound given specific attention in thepresent disclosure and via the exemplary experiments, and ischaracteristic of a large protein, as well as the following types ofcompounds: peptides; organic molecules; drug carriers; and growthfactors. Rap amycin is another bioactive agent herein disclosed incertain particular exemplary embodiments, and is characteristic ofcompounds that are: highly lipophilic, anti-restenosis agents, andanti-inflammatory agents. Heparin is another such example that ischaracterized as being: highly hydrophilic; large carbohydrate;anticoagulant agent; carbohydrate growth factor; combinedanti-coagulant-antirestenosis agent. Hydrocortisone is yet anotherexample, and is illustrative of compounds having at least the followingcharacteristics: highly lipophilic; and anti-inflammatory agents.

Accordingly, while each one of these bioactive agents represents highlybeneficial specific embodiments according to the invention, such othersubstitutes thereof, e.g. analogs or derivatives of these particularagents, or other substitutes, or combinations or blends between them orincorporating their suitable substitutes, are further considered forinclusion within the broad intended scope of the invention whereappropriate according to one of ordinary skill based at least in partupon review of this disclosure.

Still further, it is to be appreciated that the medical device coatingand forming methods and results are beneficial in that one coatingmethod and result may be used interchangeably, or in combination, withsuch varying types of compounds. The various types of compounds that acoating according to certain embodiments of the present invention may beused, interchangeably or in combination, include any one or more (e.g.combinations) of the following types of compounds: organic, inorganic,water soluble, water insoluble, hydrophilic, hydrophobic, lipophilic,large molecules, and small molecules, proteins, mono andpolysaccharides, carbohydrates, anti-restenosis compounds,anti-inflammatory compounds, anti-thrombin compounds, anti-metabolitecompounds, anti-biotic compounds, etc.

The electroless electrochemical deposition methods herein described,e.g. by reference to the Examples, results in formation of certain metalmatrices that possess features that are readily characteristic of suchformation process. For example, the metal matrix formed includes a metalin addition to another non-metal material that is derived from areducing agent as an electron donor to the metal ions formed by themetal in the electrochemical deposition fluid environment. Suchcombination of materials are not typical chrematistics of metal matricesformed by other deposition methods, e.g. sintering or electroplating. Inaddition, the structural and size characteristics of the metal matrixformed is characteristic of a process laid down on a molecular,nanometer scale, and results in features such as pore size and othersurface characteristics (e.g. smoothness, evenness, etc.) unique toother methods, e.g. versus sintering. Accordingly, it is contemplatedthat a “metal matrix formed by an electroless electrochemical process,”or other like description, is definitive of a unique and identifiablestructure.

In another regard, various additional aspects of the coating methods andobserved results related to the embodiments (e.g. by reference to theexamples) are further beneficial. For example, the coated stentsillustrated by the examples were generally observed to have metal matrixcoatings with average thicknesses of less than about 5 microns over theouter surface of the stent struts. Coating of this narrow thicknesseswas further observed to hold and elute more than 750 micrograms ofbioactive agent in one case, and in another case at least about 1milligram of bioactive agent. Further observation has revealed thatbioactive composite coatings of thicknesses of less than 1 micron, andin many instances as thin as 500 angstroms, may be achieved according tousing the methods and materials illustrated by the embodiments.

Structures having such characteristics, e.g. such density of bioactiveagent held in and released from a substrate, relative thicknesses, etc.,and in particular with respect to bioactive composite structures thatprovide an anti-restenosis agent on a stent substrate, are independentlyconsidered highly beneficial aspects of the invention, withoutlimitation as to the particular coating methods or materials used.

The embodiments herein described by reference to electrolesselectrochemical deposition are further contemplated for use incombination with other methods, including other coating methods, and inparticular other methods for coating metals (e.g. for example sinteringor electroplating). For example, a substrate to be coated usingelectroless electrochemical deposition embodiments of the invention maybe initially formed by use of an electroplating, sintering, or otherprocess. Or, such other processes may be used for surface modificationof a substrate before, after, or during electroless electrochemicaldeposition. In this regard, it is contemplated that electrolesselectrochemical deposition may be used in combination withelectroplating deposition, and/or sintering of metals to form structuresor coat surfaces.

The various embodiments described herein may be used in combination withradioactive materials, e.g. radioactive metal isotopes, such as forexample as coatings on stents or other implants to provide localradiation into tissues. For example, radiation emitting stents may beformed at least in part according to various of the methods andstructures herein described in order to radiate lumen walls to preventrestenosis. This may be accomplished instead of, or in combination with,elution of bioactive materials from the stent itself. However, inembodiments where non-radioactive metals are instead used for the metalmatrix, benefit is gained by simplicity and other improvement regardingstorage and handling, and decreased risks to patient and healthcareprovider.

In another similar regard, where reference is herein made to stents inorder to illustrate certain embodiments of the invention, other medicaldevices or other sterile structures or methods are also hereincontemplated as suitable substitutes for use.

By further reference to the various illustrative embodiments above, theinvention is further considered a broadly beneficial application ofelectroless electrochemical deposition of materials in order to coatsubstrates intended to be inserted into a living being, and therefore ina further regard broadly encompasses such processes and coated resultsin a sterile environment. In one regard, such medical devices accordingto the invention may be provided non-sterile for later sterilization byan end user or intervening party. However, the various embodimentsherein described with respect to medical devices are generallyconsidered to require such sterilization prior to their intended use,and sterile structures incorporating various of the benefits provided bythe embodiments above should be considered as independently valuableaspects of the present invention.

The various embodiments have been herein described by reference tohighly beneficial electroless electrochemical deposition methods andrelated structures. However, it is also to be appreciated that many ofthe problems solved, and beneficial results achieved, according to thesehighly beneficial embodiments may also be achieved according to othersubstitute methods, as would be apparent to one of ordinary skill basedupon a review of this disclosure. Therefore, despite the independentlyvaluable inclusion of such electroless electrochemical depositionembodiments, such substitutes are to be considered within the broadscope of certain aspects of the invention. For example, structures andmethods that provide the coating layers herein described with respect toelectrochemical deposition, e.g. including for example a metal compositematrix containing bioactive materials, may be achieved with othersubstitute methods without departing from the intended scope of suchaspects of the invention (e.g. in particular using other processes notrequiring sintering, ceramics, or polymers).

For further understanding, electroless deposition process is hereindescribed as a highly beneficial method for depositing anickel-containing coating onto a nickel-containing substrate, namely forexample an illustrative nickel-titanium substrate coated with anickel-phosphorous coating (that may include bioactive materials). Inanother example, a coating containing cobalt and chrome, and possiblyalso containing a bioactive material, may be deposited onto acobalt-chrome substrate (e.g. a stent), also by use of electrolesselectrochemical methods as described herein. However, despite theindependent benefits provided by such electroless electrochemicalmethods over other substitutes, such other substitute methods that mayprovide similar results are considered within the intended scope of theinvention with respect to the broad aspects addressing such intendedresult(s).

The terms and expressions which have been employed herein are used asterms of description and not of limitation, and there is no intention inthe use of such terms and expressions of excluding equivalents of thefeatures shown and described, or portions thereof, it being recognizedthat various modifications are possible within the scope of theinvention claimed. Moreover, any one or more features of any embodimentof the invention may be combined with any one or more other features ofany other embodiment of the invention, without departing from the scopeof the invention.

All U.S. Patent Applications, Patents and references mentioned above areherein incorporated by reference in their entirety for all purposes.

1. A method comprising: (a) providing an electrochemical solutioncomprising metal ions and a bioactive material; (b) contacting theelectrochemical solution and a substrate; and (c) forming a bioactivecomposite structure on the substrate using an electrochemical process,wherein the bioactive composite structure includes a metal matrix andthe bioactive material within the metal matrix.
 2. The method of claim 1wherein the metal ions in the electro chemical solution are derived frommetal salts, and wherein the electrochemical solution further comprisesa reducing agent.
 3. The method of claim 1 wherein the electrochemicalprocess is an electroless deposition process.
 4. The method of claim 1wherein the bioactive composite structure is in the form of a layer onthe substrate.
 5. The method of claim 1 wherein the substrate is asacrificial substrate, and wherein the method further includes: (d)removing the sacrificial substrate from the bioactive compositestructure.
 6. The method of claim 5 wherein the substrate and thebioactive composite structure form a coated stent.
 7. The method ofclaim 1 wherein the bioactive material comprises a drug.
 8. The methodof claim 1 wherein the matrix comprises nickel, chromium, gold, silver,copper, cobalt, or alloyed combinations thereof.
 9. The method of claim1 wherein the electrochemical process is an electrolytic depositionprocess.
 10. The method of claim 1 further comprising: forming a topcoaton the bioactive composite structure.
 11. The method of claim 10 whereinthe topcoat comprises a metal.
 12. The method of claim 10 wherein thetopcoat comprises a polymeric material.
 13. The method of claim 10wherein the topcoat comprises a self-assembled monolayer.
 14. Abioactive composite structure comprising: (a) a metal matrix, whereinthe metal matrix is formed using an electrochemical process; and (b) abioactive material within the metal matrix.
 15. The bioactive compositestructure of claim 14 wherein the bioactive composite structure forms astent.
 16. The bioactive composite structure of claim 14 wherein thebioactive composite structure is in the form of a layer on a stent. 17.The bioactive composite structure of claim 14 wherein the bioactivematerial comprises drugs.
 18. The bioactive composite structure of claim14 wherein the metal matrix comprises a metal alloy.
 19. The bioactivecomposite structure of claim 14 wherein an average void size of themetal matrix is less than about 100 angstroms.
 20. The bioactivecomposite structure of claim 14 wherein the bioactive compositestructure is in the form of a layer. 21.-124. (canceled)